Diseases and disorders of the digestive tract cause significant morbidity and mortality and there is a need for new therapeutics and therapeutic strategies. Diseases of the digestive tract include mucositis, aphthous stomatitis, esophagitis, inflammatory bowel disease, irritable bowel syndrome, celiac disease, trauma to the digestive tract, infections of the digestive tract and cancers of the digestive tract.
For some digestive tract diseases, there are no effective treatments available. One example of such an unmet medical need is mucositis, a serious and painful condition that results from radiation therapy and/or chemotherapy for cancer treatment. According to a recent report by the National Comprehensive Cancer Network, mucositis is the most significant adverse symptom of cancer therapy reported by patients {Bensinger et al., 2008, J Natl Compr Canc Netw, 6 Suppl 1, S1-21 quiz S22-4}. Damage can occur throughout the digestive tract and frequently results in cessation or dose reduction of the cancer therapy {Blijlevens and Sonis, 2007, Ann Oncol, 18, 817-26}. Oral mucositis presents with pain, erythema and deep, diffuse ulcers that can cause difficulty speaking, eating and swallowing and significantly impair daily functioning. Opioid analgesia, IV hydration, use of a liquid diet and total parenteral nutrition may be used in patients suffering from oral mucositis. Intestinal mucositis presents with nausea, vomiting, abdominal pain and diarrhea, sometimes with blood loss. It most commonly affects the small intestine, but is also seen in the stomach and large intestine. There is a single medication approved for the treatment of mucositis, palifermin {Blijlevens and Sonis, 2007, Ann Oncol, 18, 817-26}, but it is only used in a limited subset of patients. Therefore, there is a need for additional therapeutics for mucositis.
Another example of an unmet medical need is recurrent aphthous stomatitis (RAS), a common oral disease, affecting 5-20% of the normal population {Porter et al., 1998, Crit. Rev Oral Biol Med, 9, 306-21}. RAS presents with recurrent bouts of rounded, shallow painful ulcers on the mucosa of the mouth. The most common form is minor RAS, where the ulcers are usually less than 5 mm in diameter. The ulcers usually occur on the labial and buccal mucosa and the floor of the mouth and are uncommon on the gingival, palate or dorsum of the tongue. The lesions heal within 10-14 days. Major RAS is less common, with larger ulcers that persist for up to 6 weeks and often heal with scarring. The etiology of RAS is unknown, and there are no approved pharmacotherapies.
For some diseases of the digestive tract, treatments are already available. For example, both small molecule and biological therapies are available for the treatment of Crohn's disease and ulcerative colitis, the two forms of inflammatory bowel disease {Kozuch and Hanauer, 2008, World J Gastroenterol, 14, 354-77}. However, all of these medications have limitations, either in efficacy or in safety, and there is a need for new therapeutic approaches and strategies.
Antibodies are an important class of pharmaceuticals. Specific antibody therapeutics have been shown to be highly effective in treating cancers and autoimmune disease, and their use has been of great benefit to afflicted patients. Antibodies are generally highly specific for a particular target and thus tend to have less off-target toxicity than is seen with small molecule therapeutics.
It would be advantageous to be able to apply antibody therapeutics to diseases of the digestive tract. Most antibody therapies in current use are designed to be delivered systemically and are administered to patients by injection. Injected antibodies have been shown to be useful in the treatment of inflammatory bowel disease, and may also be useful in the treatment of other diseases of the digestive tract. However, administration of antibodies systemically may affect physiological processes throughout the body, rather than just within the digestive tract, and this may be disadvantageous for some diseases. For instance, anti-TNF antibodies used for the treatment of inflammatory bowel disease are associated with serious side effects {Lin et al., 2008, Clin Immunol, 126, 13-30}. Therefore, it would be useful to be able to apply antibody therapeutics directly to the digestive tract.
There have been two obstacles to the use of antibody therapeutics within the digestive tract. First, the digestive tract is a hostile environment for protein therapeutics, with low pH environments designed to denature ingested proteins and proteases designed to digest ingested proteins. The oral cavity contains proteases derived from the host and from resident microorganisms. Polymorphonuclear leukocytes are secreted in the crevicular fluid, and some of these cells lyse before they are swallowed, releasing lysozyme into the fluid of the oral cavity. Bacteria present as part of the normal oral flora express proteases capable of degrading immunoglobulin. These proteases include IgA1 protease, IdeS, argingipain and SpeB. The stomach is highly acidic, and contains the protease pepsin, which is active at low pH. The small intestine contains additional proteases, including trypsin and chymotrypsin. The bacteria of the large intestine further express varied proteases that degrade ingested protein. Therefore, there is a need to develop approaches to deliver antibody therapeutics to the digestive tract where the antibody will not be degraded. This invention describes methods and compositions for antibodies that have improved stability within the oral cavity and the gastrointestinal tract.
Second, many of the targets that would be useful for antibody therapeutics have not been thought to be accessible to antibody applied to the luminal surface of the digestive tract. One of the functions of the digestive tract is to create a barrier to prevent the entry into the systemic circulation of a variety of foreign agents that enter the digestive tract, including food and microorganisms. Under normal circumstances, this barrier would exclude topically applied antibody from accessing targets expressed on the basolateral face of the epithelial cells lining the digestive tract, or on the mucosa or submucosa. Therefore, there is a need to develop approaches to targeting antibodies to these targets that lie below the normal barrier of the digestive tract. This invention describes the use of antibodies to treat patients with altered permeability barriers in the digestive tract, allowing topically applied antibody to access the appropriate targets.